Neurofibromatosis is a genetic disorder that affects bone, soft tissue, skin and nervous system. It is classified into neurofibromatosis type 1 and neurofibromatosis type-2. Neurofibromatosis type-2 is caused by the mutations in neurofibromatosis type-2 gene on chromosome 22. Neurofibromatosis type-2 deficient tumors are unique in that they are slow growing tumors. The Neurofibromatosis type-2 gene encodes the merlin protein which has tumor suppressor functions.
Several pathways have been targeted for the treatment of tumors associated with neurofibromatosis type-2. U.S. Pat. No. 7,514,207 patent discloses that inhibition of p21 activated kinase (PAK) or merlin phosphorylation helps in the treatment of neurofibromatosis type-2. P21 activated kinase are well-known regulators of cytoskeletal remodelling and cell motility, but have recently also have been shown to promote cell proliferation.
WO2007143629 (“WO'629”) also discloses that inhibition of the AKT/Protein Kinase B is useful for the treatment of neurofibromatosis type-2. WO'629 is directed to a method of treating tumors resulting from the neurofibromatosis type-2 using compounds that inhibit the PI3K/AKT signalling or the proteins of the pathway. PAK and AKT/Protein kinase B inhibitors treat neurofibromatosis type-2 by merlin inactivation. So, it is beneficial only when the merlin is involved. However, these pathways may not be effective where other causes are involved.
U.S. published patent application US20140128434 discloses the treatment of neurofibromatosis type-2 by inhibiting tyrosine kinase/focal adhesion kinase (FAK) pathway. Tyrosine kinase inhibitors inhibit the activity of EGFR (Epidermal growth factor receptor), responsible for tumor growth and cell proliferation. However, it will not work where other pathways are involved in prognosis of disease.
M-TORC1 (mammalian target of rapamycin-complexi) is disclosed in Karajannis M A et. al, Neuro Oncology 2014 January, 16(2):292-7. Karajannis M A et. al discloses phase II study of everolimus (mTOR inhibitor) to treat the neurofibromatosis type-2. mTORC1 (mammalian target of rapamycin-complexi) inhibits tumor initiation and increases apoptosis. However, it is specific to only for m-TORC1 pathway.
US20120157401 discloses vascular endothelial growth factor (VEGF) and its inhibitors. It inhibits pathological production of vascular endothelial growth factor to treat neurofibromatosis type-2. VEGF (vascular endothelial growth factor) inhibitors are effective to inhibit the angiogenesis in the tumor cells.
Inhibition of the Ras protein is disclosed by A. M. Tsimberidou et. al, Journal of Clinical Oncology, 2008 A.M. The tumor suppressor protein merlin (NF2) interferes with the activation of Ras and Rac. Ras protein inhibitors such as Salirasib inhibit the Ras activation that is used to prevent cell growth and proliferation.
S Ammoun et. al, in neuro-Oncology 2011 July, 13(7):759-66 discloses a distinct pathway of neurofibromatosis type-2 treatment by inhibition of PDGFR (Platelet derived growth factor receptor). It discloses nilotinib alone or in combination with selumetinib as a drug candidate for neurofibromatosis type-2. Inhibition of platelet-derived growth factor receptor-β (PDGFR-β) leads to inhibition of extracellular-signal-regulated kinase (ERK1/2) and AKT/Protein Kinase B which prevents the schwannomatosis. However, PDGFR inhibitors again very specific and may not be effective for completely eradicating the tumor.
WO2007143630 discloses inhibition of HSP90 (Heat shock protein) for treating neurofibromatosis type-2 deficient or neurofibromatosis type-2 deficient cells with HSP90 inhibiting compound. HSP90 and/or up regulation of HSP70 is important for the proliferation and survival of NF2-deficient tumor cells. HSP90 inhibitors induce the proteasomal mediated degradation of the regulatory proteins such as kinases and transcription factors involved in proliferation, but there are many redundant factors involved in proliferation. Hence, it might not be an effective pathway for treatment of neurofibromatosis type-2.
All of the pathways discussed above have limitations and, no curative therapy or drug has been approved so far. Disease management relies almost entirely upon surgical removal of tumors. Hence, there is need to develop an effective method of treating neurofibromatosis type-2 and related conditions. The present invention is directed to overcoming these and other gaps in the art.